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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two types of human fibroblasts have been isolated from a patient with a colon cancer with metastasis, one type was derived from a healthy part of the colon, and the other one isolated from a metastasized lymph node close to the intestine. These fibroblasts have been characterized for their expression of collagens type I, III and IV, vimentin, fibronectin, alpha-smooth muscle actin, laminin and desmin. The effects of conditioned media of human colon cancer cell lines, HT29, SW1116, LS180 and HCT8R, on the metabolism of these fibroblasts were tested. All the conditioned media stimulate both types of fibroblasts, as reflected by their incorporation of radiolabelled methionine and proline. Normal fibroblasts were highly sensitive to the conditioned media as compared to the activated fibroblasts. Additionally, the production of TGF beta 1 by the four colorectal cancer cell lines has been quantified, and significant qualitative (production of latent and/or active form) and quantitative differences were observed. The effects of the conditioned media of the four tumoral cell lines and exogenous TGF beta 1 on the proliferation of the two types of fibroblasts were compared. Our data indicated that the two types of fibroblasts respond differently to TGF beta 1 whereas they are both growth stimulated by the conditioned media, apart from the LS180 conditioned medium. We conclude that if TGF beta 1 acts in the fibroblastic reaction, additional factors are required.
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PMID:[Role of TGF beta 1 in the stromal reaction to human colonic tumors]. 817 75

Tumor neovascularization is considered to be a critical step in the development of a malignant tumor. Endothelin (ET)-1 is a powerful vasoconstrictor and mitogenic peptide that is produced by many cancer cell lines. The cellular distribution of the ET components was evaluated in human colon tumors and compared to normal colon. There was more of the ET components (preproET-1, endothelin-converting enzyme-1, and ETA and ETB receptors) in adenomas and adenocarcinomas than in the normal colon. There was overproduction of preproET-1 and endothelin-converting enzyme-1 in carcinoma cells and stromal vessels, suggesting that they are a local source of ET-1. ETA receptors were present in stromal myofibroblasts of neoplastic tissue, and there were large amounts of ETB receptors in the endothelium and myofibroblasts. There was also a redistribution of alpha-smooth muscle actin-positive cells in the vascular structures of tumors. An experimental rat model of induced colon cancer treated for 30 days with bosentan, a mixed antagonist of both ET receptors, confirmed the morphological changes observed during the tumor vascularization. Our data suggest that ET-1 and its receptor play a role in colon cancer progression, with ET-1 functioning as a negative modulator of the stromal response.
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PMID:Modulation of human colon tumor-stromal interactions by the endothelin system. 1110 59

Granulation tissue involved in tissue repair and in the stroma reaction to epithelial tumors is characterized by the presence of myofibroblastic cells. It has been previously reported that granulocyte macrophage-colony stimulating factor (GM-CSF) induces a fibrotic reaction containing numerous myofibroblasts. This reaction results from a cascade of events, including stimulation of transforming growth factor-beta1 (TGF-beta1) production by macrophages which, in turn, promotes alpha-smooth muscle actin and collagen synthesis by fibroblasts. Moreover, GM-CSF is known to be expressed by many tumor cell types. In this study we have analyzed, by means of reverse transcription-polymerase chain reaction, GM-CSF mRNA expression in a progressive and a regressive rat colon carcinomas and in the corresponding cell lines, eliciting different degrees of desmoplastic reaction. We have also evaluated the expression of GM-CSF protein in selected cases. The expression of GM-CSF mRNA and, when tested, protein were higher in progressive compared to regressive cancer cells both in vivo and in vitro. We then investigated GM-CSF mRNA and protein expression in different human colon cancer cell lines known to exhibit different degrees of aggressivity in vivo. We found high levels of GM-CSF mRNA and protein in the most aggressive cell lines. Similar results were also obtained on human breast and cervical cancer cell lines. Our results are in agreement with the assumption that GM-CSF expression is correlated to tumor aggressivity. Conceivably, one of the GM-CSF actions affecting tumor progression is exerted through its influence on stroma reaction development.
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PMID:GM-CSF expression by tumor cells correlates with aggressivity and with stroma reaction formation. 1129 71

Recently, it was demonstrated that dietary omega-3 polyunsaturated fatty acids (PUFAs) induce 10-fold more metastases in number and 1000-fold in volume in an animal model of colon cancer metastasis in rat liver. It was observed that tumors of rats on a fish oil diet lacked peritumoral stroma unlike tumors in livers of rats on a low fat diet or a diet containing omega-6 PUFAs. In the present study, only one-third of the tumors in livers of rats on omega-3 PUFA diet contained peritumoral stroma, whereas peritumoral stroma was present in 87% of the tumors in livers of rats on low fat diet. To explain these findings, we tested the hypothesis that fish oil exerts a direct inhibiting effect on the formation of extracellular matrix in tumor stroma as a consequence of blocking transformation of fat storing cells into myofibroblasts. It was found with immunohistochemical analysis of desmin as marker for fat storing cells and alpha-smooth muscle actin as marker for myofibroblasts that numbers of myofibroblasts were higher in tumors containing intratumoral stroma only than in tumors containing both peritumoral and intratumoral stroma. As most of the tumors in fish oil-treated rats contained intratumoral stroma only, this suggests that transformation of fat storing cells into myofibroblasts was highest in tumor stroma of fish oil-treated rats. Therefore, it is unlikely that the lack of stroma around tumors in fish oil-treated rats is due to inhibition of transformation of fat storing cells into myofibroblasts, but lack of peritumoral stroma is rather a consequence of rapid development of tumors in livers of fish oil-treated rats.
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PMID:Promotion of colon cancer metastases in rat liver by fish oil diet is not due to reduced stroma formation. 1146 68

Epithelial-mesenchymal interactions play a pivotal role in colon cancer invasion and metastasis. We aimed at elucidating the impact of long-term cultivation on the phenotypic and functional characteristics of primary fibroblasts and their interaction with the human colon adenocarcinoma cell line LoVoC5. We used fibroblasts from human colon tumor tissue, normal human colon mucosa, rat normal colon and 2 rat colon-derived myofibroblast cell lines, MIC316 and MG. The following parameters were studied: cell shape and size, growth curve, intermediate filament expression and extracellular matrix synthesis. Coculture models with or without cell contacts were used to test the effects on LoVoC5 cell proliferation, spreading and adhesion. Irrespective of their origin, fibroblastic cells in primary cultures presented marked phenotypic and functional changes with time. Before passage 5, they presented as large, slow-growing cells expressing vimentin and alpha-smooth muscle actin; synthesizing laminin-1, fibronectin and collagens I and IV; and inducing LoVoC5 proliferation, spreading and adhesion. After passage 15, they presented as small, fast-growing cells inconstantly expressing alpha-smooth muscle actin and synthesizing mainly type I collagen. In coculture with or without cell contacts, they inhibited LoVoC5 proliferation and allowed only limited cell spreading and adhesion. Myofibroblastic cell lines presented as large, fast-growing cells expressing vimentin and alpha-smooth muscle actin and synthesizing mainly type I collagen. They had no significant effects on LoVoC5 proliferation, spreading and adhesion. Our results underline the importance of age-dependent variations in colon mesenchymal cells in culture and for the in vitro study of epithelial-mesenchymal interactions in colon cancer.
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PMID:Age-dependent variations of human and rat colon myofibroblasts in culture: Influence on their functional interactions with colon cancer cells. 1253 16

Cyclooxygenase (COX)-2, an inducible isoform of prostaglandin synthetase, has been reported to be a key molecular target of colon cancer prevention by nonsteroidal anti-inflammatory drugs. Recently, it has been shown that Helicobacter pylori (H. pylori) could induce COX-2 together with inflammatory cytokines. Although human hyperplastic gastric polyps disappeared or decreased in number and size after eradication of H. pylori, the mechanisms in this step, especially the roles of COX-2, have not been yet elucidated. The aims of the present study were to examine the expression and localization of COX-2 in human hyperplastic gastric polyps immunohistochemically. Twelve specimens of human hyperplastic gastric polyps were obtained from endoscopic polypectomy. The expression of the COX-2 protein was immunohistochemically examined on formalin-fixed and paraffin-embedded tissue sections using an anti-COX-2 antibody and an avidin-biotin complex method. Cells expressing COX-2 were further immunohistochemically identified using a specific antibody against macrophages (CD68), and myofibroblasts (alpha-smooth muscle actin). Immunoreactive COX-2 was predominantly and strongly expressed in interstitial cells in the sub-epithelial layer of 10 hyperplastic polyps. Semi-quantitative analysis revealed a significant increase in COX-2 expression in interstitial cells. The staining pattern of macrophages and myofibroblasts partly corresponded to that observed for COX-2 in hyperplastic gastric polyps. These results suggest that COX-2 in mesenchymal cells induced by H. pylori may play an important role in the tumorigenesis of human hyperplastic gastric polyps.
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PMID:Expression of cyclooxygenase-2 in human hyperplastic gastric polyps. 1458 2

Plasminogen activator inhibitor-1 (PAI-1) is up-regulated strongly in various cancer tissues, including colon cancer tissue. Highly specific rabbit polyclonal antibodies against PAI-1 were used for immunohistochemical localization of PAI-1 in 12 invasive colorectal adenocarcinomas. PAI-1 immunoreactivity was observed in endothelial cells of some vessels located in the submucosa and in several fibroblast-like cells located at the invasive front. No PAI-1 immunoreactivity was seen in cancer cells in any of the 12 cases. Double immunofluorescence using the PAI-1 antibodies together with antibodies against alpha-smooth muscle actin for myofibroblast/smooth muscle cells and CD34 for endothelial cells showed that more than 80% of the PAI-1-positive fibroblast-like cells in all 12 cases were myofibroblasts. In 4 of 12 cases, a few of the PAI-1-positive fibroblast-like cells in the invasive front were CD34+. We conclude that the majority of PAI-1-positive fibroblast-like cells located at the leading edge of the invasive colon cancers are myofibroblasts.
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PMID:Leading-edge myofibroblasts in human colon cancer express plasminogen activator inhibitor-1. 1532 43

Tissue inhibitor of matrix metalloproteases 1 (TIMP-1) inhibits the proteolytic activity of matrix metalloproteases and hereby prevents cancer invasion. However, TIMP-1 also possesses other functions such as inhibition of apoptosis, induction of malignant transformation and stimulation of cell-growth. We have previously demonstrated that TIMP-1 is elevated in blood from colorectal cancer patients and that high TIMP-1 levels predict poor prognosis. To clarify the role of TIMP-1 in colorectal tumorigenesis, the expression pattern of TIMP-1 in benign and malignant colorectal tumors was studied. In all of 24 cases of colorectal adenocarcinoma TIMP-1 mRNA was detected by in situ hybridization. In all cases TIMP-1 expression was found in fibroblast-like cells located at the invasive front but was seen only sporadically in normal mucosa. No TIMP-1 mRNA was seen in any of the cases in benign or malignant epithelial cells, in vascular cells or smooth muscle cells. Comparison of sections processed for TIMP-1 in situ hybridization with sections immunohistochemically stained with antibodies against TIMP-1 showed good correlation between TIMP-1 mRNA and immunoreactivity. Combining TIMP-1 in situ hybridization with immunohistochemical staining for alpha-smooth muscle actin or CD68 showed TIMP-1 mRNA in myofibroblasts but not in macrophages. TIMP-1 mRNA was detected in 2 of 7 adenomatous polyps in the adenoma area: in both cases associated with focal stromal inflammation at the epithelial-stromal interface. In conclusion, TIMP-1 expression is a rare event in benign human colon tissue but is highly expressed by myofibroblasts in association with invading colon cancer cells.
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PMID:Localization of tissue inhibitor of metalloproteinases 1 (TIMP-1) in human colorectal adenoma and adenocarcinoma. 1538 9

Colon carcinoma invasiveness is a process involving cell-cell and cell-matrix alterations, local proteolysis of the ECM (extracellular matrix) or changes in cytokine and growth factor levels. In order to evaluate the role of TGF-beta1 (transforming growth factor-beta1) and small G protein RhoA in tumour progression, the influence of TGF-beta1 treatment or RhoA-associated kinase inhibitor on the production of NO (nitric oxide) and MMP-2 and MMP-9 (metalloproteinases-2 and -9) was analysed in three human colon adenocarcinoma cell lines (HT29, LS180, SW948) representing different stages of tumour development. All the tested cell lines produced low amounts of MMP-2 and MMP-9. rhTGF-beta1 and the synthetic Rho kinase inhibitor (Y-27632) decreased MMP-2 secretion by colon cancer cells, especially in the most advanced stage of colon cancer. rhTGF-beta1 decreased NO secretion by cells, while Y-27632 had no effect on it. Immunoblotting with anti-RhoA antibodies followed by densitometry revealed that RhoA levels were slightly increased after incubation of colon carcinoma cells (SW948) with rhTGF-beta1. rhTGF-beta1 induced alpha-smooth muscle actin (alpha-SMA) expression, especially in high Duke's grade of colon cancer, while Y-27632 blocked it. Summing up, in colon carcinoma cells, TGF-beta1 and RhoA protein may regulate tumour invasiveness measured as MMP, NO and alpha-SMA expression or assayed using motility data and may be a good target for cancer therapy.
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PMID:Transforming growth factor-beta1 modulates metalloproteinase-2 and -9, nitric oxide, RhoA and alpha-smooth muscle actin expression in colon adenocarcinoma cells. 1994 19

Cancer-associated fibroblasts (CAFs) represent the predominant cell type of the neoplastic stroma of solid tumors, yet their biology and functional specificity for cancer pathogenesis remain unclear. We show here that primary CAFs from colorectal liver metastases express several inflammatory, tumor-enhancing factors, including interleukin (IL)-6 and monocyte-chemoattractant protein (MCP)-1. Both molecules were intensely induced by TNF-alpha on the transcript and protein level, whereas PDGF-BB, TGF-beta1 and EGF showed no significant effects. To verify their potential specialization for metastasis progression, CAFs were compared to fibroblasts from non-tumor liver tissue. Interestingly, these liver fibroblasts (LFs) displayed similar functions. Further analyses revealed a comparable up-regulation of intercellular adhesion molecule-1 (ICAM-1) by TNF-alpha, and of alpha-smooth muscle actin, by TGF-beta1. Moreover, the proliferation of both cell types was induced by PDGF-BB, and CAFs and LFs displayed an equivalent migration towards HT29 colon cancer cells in Boyden chamber assays. In conclusion, colorectal liver metastasis may be supported by CAFs and resident fibroblastic cells competent to generate a prometastatic microenvironment through inflammatory activation of IL-6 and MCP-1.
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PMID:TNF-alpha similarly induces IL-6 and MCP-1 in fibroblasts from colorectal liver metastases and normal liver fibroblasts. 2061 59


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